Fragile X syndrome (FXS) is the most common inherited form of an intellectual disability. Children with FXS have been found to have a developmental impairment in the performance of learned skilled limb movements. Motor skill learning is thought to require synaptic plasticity in the primary motor cortex (M1). To better understand how neuronal communication changes with motor learning, it is necessary to determine if learning can induce changes in number, morphology, efficacy, and molecular composition of synapses. FXS results from mutation that causes silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP). Here we will use the fmr1 KO mouse, a murine model for FXS, to study the mechanisms of learning in the primary motor cortex. Our goal is to understand how fmr1 contributes to regulation of synaptic plasticity in the motor cortex and thus elucidate the mechanisms of motor skill learning deficits in the fmr1 KO. We will combine behavioral, electrophysiological, pharmacological, 2-photon imaging and molecular approaches to characterize the changes that occur at synapses in M1 following the learning of a new motor skill in the fmr1 KO mouse. This work is expected to provide important knowledge to develop therapies for FXS and other neurodevelopmental disorders such as autism, a mission of the NIH. !

Public Health Relevance

Fragile X syndrome (FXS) and autism patients have a developmental impairment in the performance of learned skilled limb movements. It is therefore critical to determine the cellular mechanisms that govern motor learning in normal and developmentally abnormal brain. Here we will study the mechanism of motor learning in a mouse model of FXS. This will help to determine the neurobiological basis of the motor skill deficits in FXS and help identify therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD067218-01A1
Application #
8297444
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Urv, Tiina K
Project Start
2012-03-15
Project End
2017-02-28
Budget Start
2012-03-15
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$308,138
Indirect Cost
$100,638
Name
University of Nebraska Medical Center
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Padmashri, Ragunathan; Reiner, Benjamin C; Suresh, Anand et al. (2013) Altered structural and functional synaptic plasticity with motor skill learning in a mouse model of fragile X syndrome. J Neurosci 33:19715-23